Methods and compositions for the treatment of neuropathies and related disorders

Abstract

The present invention provides novel compositions and methods for treating symptoms associated with neuropathic disorders such as hyperalgesia, allodynia, and parasthesias, using a 1-aryl-3-azabicyclo[3.1.0] hexane. The invention further relates to the use of 1-aryl-3-azabicyclo[3.1.0] hexanes in pharmaceutical compositions and methods for treating neuropathic disorders and related symptoms in mammals. Patients amenable to treatment according to the invention include those suffering from diabetic neuropathies, post-herpetic neuralgia, trigeminal neuralgia, chronic lower back pain, sciatica, idiopathic and post-traumatic neuropathies, HIV-associated neuropathic pain, among many other neuropathic disorders and related symptoms.

1 . A method for preventing or treating a neuropathic disorder in a mammalian subject comprising administering to said subject an effective amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein Ar is a phenyl or other aromatic group having at least one substitution on the aryl ring, and wherein R is selected from hydrogen, C 1-6  alkyl, halo(C 1-6 )alkyl, C 3-9  cycloalkyl, C 1-5  alkoxy(C 1-6 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, carbamate, halo(C 1-3 )alkoxy(C 1-6 )alkyl, C 1-3  alkylamino(C 1-6 )alkyl, and di(C 1-3 )alkylamino(C 1-6 )alkyl, cyano(C 1-6 )alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl.  
   
   
       2 . The method of  claim 1 , wherein the compound is selected from bicifadine, enantiomers of bicifadine, salts of bicifadine, prodrugs of bicifadine, polymorphs, hydrates, and solvates of bicifadine, and combinations thereof.  
   
   
       3 . The method of  claim 2 , wherein the compound is bicifadine HCl.  
   
   
       4 . The method of  claim 2 , wherein the compound comprises a (+) enantiomer of bicifadine.  
   
   
       5 . The method of  claim 4 , wherein the compound is administered in a formulation that is substantially free of a (−) enantiomer of bicifadine.  
   
   
       6 . The method of  claim 2 , wherein the compound comprises a (−) enantiomer of bicifadine.  
   
   
       7 . The method of  claim 6 , wherein the compound is administered in a formulation that is substantially free of a (+) enantiomer of bicifadine.  
   
   
       8 . The method of  claim 2 , wherein the compound comprises a polymorph B form of bicifadine.  
   
   
       9 . The method of  claim 8 , wherein the compound is administered in a formulation that is substantially free of a polymorph A form of bicifadine.  
   
   
       10 . The method of  claim 1 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable, active salts, solvates, hydrates, polymorphs, enantiomers, and prodrugs thereof.  
   
   
       11 . The method of  claim 1 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable, active salts, solvates, hydrates, polymorphs, enantiomers, and prodrugs thereof.  
   
   
       12 . A method for preventing or treating a neuropathic disorder in a mammalian subject comprising administering to said subject an effective amount of a compound of formula III  
     
       
         
         
             
             
         
       
     
     wherein R is selected from C 1-6  alkyl, halo(C 1-6 )alkyl, C 3-9  cycloalkyl, C 1-5  alkoxy(C 1-6 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, carbamate, halo(C 1-3 )alkoxy(C 1-6 )alkyl, C 1-3  alkylamino(C 1-6 )alkyl, and di(C 1-3 )alkylamino(C 1-6 )alkyl, cyano(C 1-6 )alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl; and  
     wherein R 1  is selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, and trifluoromethoxy.  
   
   
       13 . The method of  claim 12 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable, active salts, solvates, hydrates, polymorphs, enantiomers, and prodrugs thereof.  
   
   
       14 . A method for preventing or treating a neuropathic disorder in a mammalian subject comprising administering to said subject an effective amount of a compound of formula IV  
     
       
         
         
             
             
         
       
     
     wherein R is selected from C 1-6  alkyl, halo(C 1-6 )alkyl, C 3-9  cycloalkyl, C 1-5  alkoxy(C 1-6 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, carbamate, halo(C 1-3 )alkoxy(C 1-6 )alkyl, C 1-3  alkylamino(C 1-6 )alkyl, and di(C 1-3 )alkylamino(C 1-6 )alkyl, cyano(C 1-6 )alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl.  
   
   
       15 . The method of  claim 14 , wherein the compound is selected from:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable, active salts, solvates, hydrates, polymorphs, enantiomers, and prodrugs thereof.  
   
   
       16 . A method for preventing or treating one or more symptom(s) resulting from a neuropathic disorder in a mammalian subject comprising administering to said subject an effective amount of a 1-aryl-3-azabicyclo[3.1.0]hexane.  
   
   
       17 . The method of  claim 16 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is selected from bicifadine, enantiomers of bicifadine, salts of bicifadine, prodrugs of bicifadine, polymorphs, hydrates, and solvates of bicifadine, and combinations thereof.  
   
   
       18 . The method of  claim 17 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is bicifadine HCl.  
   
   
       19 . A method for preventing or treating one or more symptom(s) resulting from a neuropathic disorder in a mammalian subject comprising administering to said subject an effective amount of a compound of formula V  
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are each selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, and trifluoromethoxy.  
   
   
       20 . The method of  claim 19 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.  
   
   
       21 - 71 . (canceled)